Impact of APOL1 Genetic Variants on HIV-1 Infection and Disease Progression

Apolipoprotein L1 (APOL1) has broad innate immune functions and has been shown to restrict HIV replication in vitro by multiple mechanisms. Coding variants in APOL1 are strongly associated with HIV-associated nephropathy (HIVAN) in persons with untreated HIV infection; however, the mechanism by which APOL1 variant protein potentiates renal injury in the presence of high viral load is not resolved. Little is known about the association of APOL1 genotypes with HIV viral load, HIV acquisition, or progression to AIDS. We assessed the role of APOL1 coding variants on HIV-1 acquisition using the conditional logistic regression test, on viral load using the t-test or ANOVA, and on progression to AIDS using Cox proportional hazards models among African Americans enrolled in the ALIVE HIV natural history cohort (n = 775). APOL1 variants were not associated with susceptibility to HIV-1 acquisition by comparing genotype frequencies between HIV-1 positive and exposed or at-risk HIV-1 uninfected groups (recessive model, 12.8 vs. 12.5%, respectively; OR 1.02, 95% CI 0.62–1.70). Similar null results were observed for dominant and additive models. APOL1 variants were not associated with HIV-1 viral load or with risk of progression to AIDS [Relative hazards (RH) 1.33, 95% CI 0.30–5.89 and 0.96, 95% CI 0.49–1.88, for recessive and additive models, respectively]. In summary, we found no evidence that APOL1 variants are associated with host susceptibility to HIV-1 acquisition, set-point HIV-1 viral load or time to incident AIDS. These results suggest that APOL1 variants are unlikely to influence HIV infection or progression among individuals of African ancestry

Renal and Cardiovascular Morbidities Associated with APOL1 Status among African-American and Non-African-American Children with Focal Segmental Glomerulosclerosis

Background and objectives: African American (AA) children with focal segmental glomerulosclerosis (FSGS) have later onset disease that progresses more rapidly than in non-AA children. It is unclear how APOL1 genotypes contribute to kidney disease risk, progression and cardiovascular morbidity in children. Design, setting, participants, & measurements: We examined the prevalence of APOL1 genotypes and associated cardiovascular phenotypes among children with FSGS in the Chronic Kidney Disease in Children (CKiD) study; an ongoing multicenter prospective cohort study of children aged 1-16 years with mild to moderate kidney disease.Results: A total of 140 AA children in the CKiD study were genotyped. HR APOL1 genotypes were present in 24% of AA children (33/140) and were associated with FSGS, p 3 mg/L (33% vs. 15%, p=0.12) and obesity (48% vs. 19%, p=0.01). There were no differences in glomerular filtration rate, hemoglobin, iPTH, or calcium-phosphate product. Conclusions: AA children with HR APOL1 genotype and FSGS have increase prevalence of obesity and LVH despite a later age of FSGS onset, while adjusting for socioeconomic status. Treatment of obesity may be an important component of CKD and LVH management in this population

MHC class I chain-related protein A shedding in chronic HIV-1 infection is associated with profound NK cell dysfunction

Natural killer (NK) cells play a critical role in host defense against viral infections. However chronic HIV-1 infection is associated with an accumulation of dysfunctional NK cells, that poorly control viral replication. The underlying mechanisms for this NK cell mediated dysfunction are not understood. Certain tumors evade NK cell mediated detection by dampening NK cell activity through the downregulation of NKG2D, via the release of soluble NKG2D-ligands, resulting in a potent suppression of NK cell function. Here we show that chronic HIV-1 infection is associated with a specific defect in NKG2D-mediated NK cell activation, due to reduced expression and transcription of NKG2D. Reduced NKG2D expression was associated with elevated levels of the soluble form of the NKG2D-ligand, MICA, in patient sera, likely released by HIV+CD4+ T cells. Thus, like tumors, HIV-1 may indirectly suppress NK cell recognition of HIV-1-infected CD4+ T cells by enhancing NKG2D-ligand secretion into the serum resulting in a profound impairment of NK cell function

The HLA-B*57:01 allele corresponds to a very large MHC haploblock likely explaining its massive effect for HIV-1 elite control

IntroductionWe have reanalyzed the genomic data of the International Collaboration for the Genomics of HIV (ICGH), centering on HIV-1 Elite Controllers.MethodsWe performed a genome-wide Association Study comparing 543 HIV Elite Controllers with 3,272 uninfected controls of European descent. Using the latest database for imputation, we analyzed 35,552 Single Nucleotide Polymorphisms (SNPs) within the Major Histocompatibility Complex (MHC) region.ResultsOur analysis identified 2,626 SNPs significantly associated (p<5. 10-8) with elite control of HIV-1 infection, including well-established MHC signals such as the rs2395029-G allele which tags HLA-B*57:01. A thorough investigation of SNPs in linkage disequilibrium with rs2395029 revealed an extensive haploblock spanning 1.9 megabases in the MHC region tagging HLA-B*57:01, comprising 379 SNP alleles impacting 72 genes. This haploblock contains damaging variations in proteins like NOTCH4 and DXO and is also associated with a strong differential pattern of expression of multiple MHC genes such as HLA-B, MICB, and ZBTB12. The study was expanded to include two cohorts of seropositive African-American individuals, where a haploblock tagging the HLA-B*57:03 allele was similarly associated with control of viral load. The mRNA expression profile of this haploblock in African Americans closely mirrored that in the European cohort.DiscussionThese findings suggest that additional molecular mechanisms beyond the conventional antigen-presenting role of class I HLA molecules may contribute to the observed influence of HLA-B*57:01/B*57:03 alleles on HIV-1 elite control. Overall, this study has uncovered a large haploblock associated with HLA-B*57 alleles, providing novel insights into their massive effect on HIV-1 elite control

Genome-Wide Association Study Identifies Single Nucleotide Polymorphism in DYRK1A Associated with Replication of HIV-1 in Monocyte-Derived Macrophages

Background: HIV-1 infected macrophages play an important role in rendering resting T cells permissive for infection, in spreading HIV-1 to T cells, and in the pathogenesis of AIDS dementia. During highly active anti-retroviral treatment (HAART), macrophages keep producing virus because tissue penetration of antiretrovirals is suboptimal and the efficacy of some is reduced. Thus, to cure HIV-1 infection with antiretrovirals we will also need to efficiently inhibit viral replication in macrophages. The majority of the current drugs block the action of viral enzymes, whereas there is an abundance of yet unidentified host factors that could be targeted. We here present results from a genome-wide association study identifying novel genetic polymorphisms that affect in vitro HIV-1 replication in macrophages. Methodology/Principal Findings: Monocyte-derived macrophages from 393 blood donors were infected with HIV-1 and viral replication was determined using Gag p24 antigen levels. Genomic DNA from individuals with macrophages that had relatively low (n = 96) or high (n = 96) p24 production was used for SNP genotyping with the Illumina 610 Quad beadchip. A total of 494,656 SNPs that passed quality control were tested for association with HIV-1 replication in macrophages, using linear regression. We found a strong association between in vitro HIV-1 replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A (p = 2.16×10-5). While the association was not genome-wide significant (p<1×10-7), we could replicate this association using monocyte-derived macrophages from an independent group of 31 individuals (p = 0.0034). Combined analysis of the initial and replication cohort increased the strength of the association (p = 4.84×10-6). In addition, we found this SNP to be associated with HIV-1 disease progression in vivo in two independent cohort studies (p = 0.035 and p = 0.0048). Conclusions/Significance: These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo. © 2011 Bol et al

WITHDRAWN: Balancing the genetic risk of APOL1 kidney disease variants

International audienceAfrican-Americans exhibit an excess risk for chronic and end-stage kidney disease compared to the non-African populations. Two APOL1 genetic variants were shown to account for the majority of this racialdisparity in glomerulopathies and other non-diabetic kidney disease. The high-risk genotype has onlybeen reported in populations with recent African ancestry (14 % in African-Americans and up to morethan 30 % in West Africa). In less than 10 years, the community has accumulated extensive knowledge onAPOL1 and its genetic variants, from their positive selection for resistance against African trypanosomesto potential molecular mechanisms of podocyte injury. Finally, APOL1 associations with kidneytransplantation outcomes and with postdonation end-stage kidney disease in living donors have pavedthe way for a personalized medicine implementation of APOL1 genotyping

Lessons from CKD-Related Genetic Association Studies\textendashMoving Forward

International audienc

Identification of a common transcriptional signature for regulatory B cells in Humans and Mice

International audienceRegulatory B cells (Bregs) have been described in mice and humans for their ability to regulate inflammation through a variety of mechanisms in different pathological situations. Up to date, no consensual and common Breg phenotype has been described, and whether there is a Breg lineage commitment or if they acquire their function under certain environmental conditions remains unknown. To address these points, we performed a sample size weighted meta-analysis of publicly available transcriptomic data from 4 different Bregs studies in humans and 6 Bregs studies in mice

Large-Scale “OMICS” Studies to Explore the Physiopatholgy of HIV-1 Infection

International audienceIn this review, we present the main large-scale experimental studies that have been performed in the HIV/AIDS field. These "omics" studies are based on several technologies including genotyping, RNA interference, and transcriptome or epigenome analysis. Due to the direct connection with disease evolution, there has been a large focus on genotyping cohorts of well-characterized patients through genome-wide association studies (GWASs), but there have also been several in vitro studies such as small interfering RNA (siRNA) interference or transcriptome analyses of HIV-1-infected cells. After describing the mojor results obtained with these omics technologies-including some with a high relevance for HIV-1 treatment-we discuss the next steps that the community needs to embrace in order to derive new actionable therapeutic or diagnostic targets. Only integrative approaches that combine all big data results and consider their complex interactions will allow us to capture the global picture of HIV molecular pathogenesis. This novel challenge will require large collaborative efforts and represents a huge open field for innovative bioinformatics approaches

APOL1-Associated Nephropathy: A Key Contributor to Racial Disparities in CKD

International audienceGenetic methodologies are improving our understanding of the pathophysiology in diverse diseases. Breakthroughs have been particularly impressive in nephrology, for which marked disparities exist in rates and etiologic classifications of end-stage kidney disease between African Americans and European Americans. Discovery of the apolipoprotein L1 gene (APOL1) association with focal segmental glomerulosclerosis, human immunodeficiency virus (HIV)-associated nephropathy, lupus nephritis, sickle cell nephropathy, and solidified glomerulosclerosis, as well as more rapid failure of transplanted kidneys from donors with APOL1 renal-risk genotypes, has improved our understanding of nondiabetic nephropathy. Environmental factors acting through natural selection in sub-Saharan African populations likely underlie this association. This article describes the discovery of chromosome 22q renal-risk variants and their worldwide distribution, reviews the epidemiology and pathology of APOL1-associated nephropathies, and explores several proposed mechanisms of kidney injury identified in cell culture and animal models. Detection of APOL1 associations with kidney diseases and delineation of injury pathways brings hope for effective treatment for these kidney diseases